GLYCOSAMINOGLYCAN

LYCOSAMINOGLYCAN
and PROTEOGLYCANS
and ROTEOGLYCANS

CHUA, Ma. Aurea

CHUA, Ma. Aurea
CIRILO, Gerry Marc
CIRILO, Gerry Marc
CLARITO, Eunice Lovelle
CLARITO, Eunice Lovelle
CLARITO, Kristy Ann
CLARITO, Kristy Ann

Group 6, MD-I A2
Group 6, MD-I A2
LEARNING OBJECTIVES:

At
At the
the end
end of
of the
the clinical
clinical conference,
conference, the
the students
students will
will be
be able
able
to:
to:
Define
Define what
what are
are glycosaminoglycans
glycosaminoglycans and and proteoglycans
proteoglycans
and
and their
their biologic
biologic importance.
importance.
Understand
Understand thethe biosynthesis
biosynthesis of
of glycosaminoglycans
glycosaminoglycans and and
differentiate
differentiate each
each type.
type.
Know
Know the
the different
different mucoplysaccharidoses,
mucoplysaccharidoses, identify
identify the
the
deficient
deficient enzyme
enzyme inin each
each type
type and
and its
its clinical
clinical
characteristics.
characteristics.
Know
Know the
the role
role of
of glycosaminoglycans
glycosaminoglycans in in Cancer,
Cancer,
Atherosclerosis
Atherosclerosis andand Arthritis.
Arthritis.
GLYCOSAMINOGLYCANS and their biologic
importance

GAGs
GAGs are
are long
long unbranched
unbranched polysaccharides
polysaccharides
containing
containing aa repeating
repeating dissacharide
dissacharide units
units
Amino
Amino sugars
sugars ––
N-acetylgalactosamine
N-acetylgalactosamine (Gal(Gal NAc)
NAc) or
or
N-acetylglucosamine
N-acetylglucosamine (Glc(Glc NAc)
NAc)
Uronic
Uronic acids
acids –– glucuronic
glucuronic acid
acid (Glc
(Glc UA)
UA)
or
or iduronic
iduronic acid
acid (Id
(Id UA)
UA)
GLYCOSAMINOGLYCANS and their biologic
importance

Sulfate
Sulfate groups
groups
Hyaluronic
Hyaluronic acid,
acid, chondroitin
chondroitin sulfates,
sulfates, keratin
keratin
sulfates
sulfates II and
and II,
II, heparin
heparin and
and heparin
heparin sulfates
sulfates
and
and dermatan
dermatan sulfate
sulfate
The
The majority
majority of
of GAGs
GAGs inin the
the body
body are
are linked
linked to
to
core
core proteins
proteins forming
forming proteoglycans
proteoglycans
Functions of GAGs and Proteoglycans

Acts
Acts as
as structural
structural component
component ofof the
the ECM
ECM
Have
Have specific
specific interactions
interactions with
with collagen,
collagen, elastin,
elastin,
fibronectin,
fibronectin, laminin
laminin and
and other
other proteins
proteins such
such as
as
growth
growth factors
factors
As
As polyanions,
polyanions, bind
bind polycations
polycations and
and cations
cations
Contribute
Contribute toto characteristic
characteristic turgor
turgor ofof various
various
tissues
tissues
Functions of GAGs and Proteoglycans

Acts
Acts as
as sieves
sieves inin the
the ECM
ECM
Facilitate
Facilitate cell
cell migration
migration (HA)(HA)
Have
Have role
role in
in compressibility
compressibility of of cartilage
cartilage in
in
weight-bearing
weight-bearing (HA,(HA, CS)
CS)
Play
Play aa role
role in
in corneal
corneal transparency
transparency (KS1
(KS1 and
and DS)
DS)
Have
Have structural
structural role
role in
in sclera
sclera (DS)
(DS)
Functions of GAGs and Proteoglycans

Act
Act as
as anticoagulant
anticoagulant (heparin)
(heparin)
Component
Component ofof plasma
plasma membranes
membranes (HS)
(HS)
Determine
Determine charge-selectiveness
charge-selectiveness of
of renal
renal
glumerulus
glumerulus (HS)
(HS)
Components
Components ofof synaptic
synaptic and
and other
other vesicles
vesicles
Biosynthesis of GAGs

A.
A. Attachment
Attachment to
to core
core proteins:
proteins:
1.
1. O-glycosidic
O-glycosidic bond
bond between
between xylose
xylose (Xyl)
(Xyl) and
and Ser
Ser
through
through UDP-xylose
UDP-xylose

Gal Gal 1,3 Xyl O-Ser

1,4
Link trisaccharide
Biosynthesis of GAGs

2.
2. O-
O- glycosidic
glycosidic bond
bond between
between GalNAC
GalNAC (N-
(N-
acetylgalactosamine)
acetylgalactosamine) and
and Ser
Ser (Thr)
(Thr) through
through
UDP-GalNAC
UDP-GalNAC

3.
3. N-glycosylamine
N-glycosylamine bond
bond between
between GlcNAc
GlcNAc (N-
(N-
acetylglucosamine)
acetylglucosamine) and
and the
the amide
amide nitrogen
nitrogen of
of
Asn
Asn through
through dolichol-P-P-oligosaccharide
dolichol-P-P-oligosaccharide
Biosynthesis of GAGs

B.
B. CHAIN
CHAIN ELONGATION
ELONGATION

Nucleotide
Nucleotide sugars
sugars (UDP-xylose,
(UDP-xylose, UDP-GalNAC)
UDP-GalNAC)
Highly
Highly specific
specific glucosyltransferases
glucosyltransferases
“one
“one enzyme,
enzyme, one
one linkage”
linkage”
Biosynthesis of GAGs

C.
C. CHAIN
CHAIN TERMINATION
TERMINATION

Sulfation
Sulfation (( certain
certain positions
positions of
of sugar)
sugar)
Progression
Progression of of the
the growing
growing GAG
GAG chain
chain away
away
from
from the
the membrane
membrane site site where
where catalysis
catalysis occurs
occurs
Biosynthesis of GAGs

D.
D. FURTHER
FURTHER MODIFICATIONS
MODIFICATIONS

Introduction
Introduction of
of sulfate
sulfate groups
groups unto
unto GalNAc
GalNAc and
and
other
other moieties
moieties through
through sulfotransferases
sulfotransferases and
and the
the use
use
of
of 3’-phosphoadenosine-5’-phosphosulfate
3’-phosphoadenosine-5’-phosphosulfate (PAPS)
(PAPS)

Conversion
Conversion of
of GlcUA
GlcUA to
to IdUA
IdUA residues
residues through
through
epimerase
epimerase
Major Properties of GAGs
GAG SUGARS SULFATE LINKAGE OF PROTEIN
HA GlcNAc, GlcUA Nil No firm evidence
CS GalNAc, GlcUA GalNAc Xyl-Ser; associated with
HA via link proteins
KS I GlcNAc, Gal GlcNAc GlcNAc-Asn
KS II GlcNAc, Gal GlcNAc GalNAc- Thr
Heparin GlcN, IdUA GlcN Ser
GlcN
IdUA

Heparan sulfate GlcN, GlcUA GlcN Xyl-Ser

Dermatan sulfate GalNAc, IdUA, GalNAc Xyl-Ser
(GlcUA) IdUA
Synthesis of Choindroitin Sulfate
Proteoglycan
Xyl,
Xyl, xylose;
xylose;
Gal,
Gal, galactose;
galactose;
GlcUA,
GlcUA, glucuronic
glucuronic acid;
acid;
GalNAC,
GalNAC, N-acetylgalactosamine;
N-acetylgalactosamine;
PAPS,
PAPS, 3’-phosphoadenosine-5’-phosphosulfate
3’-phosphoadenosine-5’-phosphosulfate
*-(
*-( UDP-GalNAc,
UDP-GalNAc, UDP-GlcUA,
UDP-GlcUA, PAPS)
PAPS)n
n
Structures of GAGs

Hyaluronic
Hyaluronic Acid
Acid
β 1,4 β 1,3 β 1,4 β 1,3 β 1,4
Hyaluronic Acid GlcUA GlcNAc GlcUA GlcNAc
 Structures of GAGs

Dermatan
Dermatan sulfate
sulfate

β 1, 4 α 1, 3 β 1, 4 β 1, 3 β 1, 4 β 1, 3 β 1, 3 β 1, 4 β
Dermatan IdUA GalNAc GlcUA GalNAc GlcUA Gal Gal Xyl
Ser
Sulfate 2- Sulfate 4-Sulfate
Structures of GAGs

Heparin
Heparin
6-Sulfate
α 1, 4 α 1, 4 α 1, 4 β 1, 4 α 1, 4 β 1, 3 β 1, 3 β 1, 4 β
Heparin IdUA GlcN GlcUA GlcNAC GlcUA Gal Gal Xyl
Ser
2-Sulfate S03-
Structures of GAGs

Heparan
Heparan sulfate
sulfate
6-Sulfate
α 1, 4 α 1, 4 α 1, 4 β 1, 4 α 1, 4 β 1, 3 β 1, 3 β 1, 4 β
Heparan: IdUA GlcN GlcUA GlcNAC GlcUA Gal Gal Xyl Ser
Sulfate
Ac
Structures of GAGs

Keratan
Keratan Sulfate
Sulfate II
β 1,4 β 1,3 β 1,4 β 1,3 (GlcNAc, Man) β
Keratan Sulfate I GlcNAc Gal GlcNAc Gal GlcNAc Asn

6-Sulfate 6-Sulfate
Structures of GAGs

Keratan
Keratan Sulfate
Sulfate II
II
β 1,4 β 1,3 β 1,4 β 1,3 1, 6 α
Keratan Sulfate I GlcNAc Gal GlcNAc Gal GalNAc Thr
(Ser)
6-Sulfate 6-Sulfate Gal-NeuAC
Mucopolysaccharidoses
Mucopolysaccharidoses
Mucopolysaccharidoses
Mucopolysaccharidoses are are aa group
group ofof metabolic
metabolic
disorders
disorders caused
caused byby the
the absence
absence or or malfunctioning
malfunctioning of of
lysosomal
lysosomal enzymes
enzymes needed
needed toto break
break down
down molecules
molecules
called
called glycosaminoglycans
glycosaminoglycans -- long long chains
chains ofof sugar
sugar
carbohydrates
carbohydrates in in each
each of
of our
our cells
cells that
that help
help build
build bone,
bone,
cartilage,
cartilage, tendons,
tendons, corneas,
corneas, skin
skin and
and connective
connective tissue.
tissue.
Depending
Depending on on the
the specific
specific enzyme
enzyme deficiency,
deficiency, the
the
catabolism
catabolism ofof one
one or
or more
more GAGs
GAGs may may bebe blocked.
blocked.
Clinical
Clinical features
features vary
vary depending
depending on on the
the tissue
tissue
distribution
distribution of
of the
the affected
affected substrate
substrate and
and the
the degree
degree ofof
enzyme
enzyme deficiency.`
deficiency.`
In
In Morquio
Morquio syndrome
syndrome (mucopolysaccharidosis
(mucopolysaccharidosis typetype IV),
IV), the
the
degradation
degradation of
of KS
KS is
is defective
defective because
because of
of deficiency
deficiency of
of either
either N
N
-acetyl-galactosamine-6-sulfate
-acetyl-galactosamine-6-sulfate sulfatase
sulfatase (GALNS
(GALNS gene)
gene) in
in
Morquio
Morquio syndrome
syndrome type
type IVA
IVA or
or ββ –galactosidase
–galactosidase (GLB1
(GLB1 gene)
gene) in
in
Morquio
Morquio syndrome
syndrome type
type IVB.
IVB.
Type Main diseases Deficient enzyme Accumulated Symptoms Incidence
products
MPS I Hurler syndrome α-L-iduronidase Heparan sulfate Mental retardation, Micrognathia, Coarse 1 in 100.000
Dermatan sulfate facies,Macroglossia,Retinal degeneration,
Corneal clouding,Cardiomyopathy,
Hepatosplenomegaly

MPS II Hunter syndrome Iduronate sulfatase Heparan sulfate Mental retardation 1 in 250.000
Dermatan sulfate

MPS Sanfilippo syndrome A Heparan sulfamidase Heparan sulfate Developmental delay 1 in 280,000
III Severe hyperactivity to
Sanfilippo syndrome B N-acetylglucosaminidase Spasticity 1 in 50,000
Motor dysfunction
Death by the second decade
Sanfilippo syndrome C Acetyl-CoA:alpha-
glucosaminide
acetyltransferase

Sanfilippo syndrome D N-acetylglucosamine 6-

sulfatase

MPS Morquio syndrome A Galactose-6-sulfate Keratan sulfate Severe skeletal dysplasia 1 in 75,000
IV sulfatase Chondroitin 6- Short stature
sulfate Motor dysfunction

Morquio syndrome B Beta-galactosidase Keratan sulfate

MPS Maroteaux-Lamy N-acetylgalactosamine-4- Dermatan sulfate Severe skeletal dysplasia, Short stature,
VI syndrome sulfatase Motor dysfunction,Kyphosis,Heart defects

MPS Sly syndrome β-glucuronidase Heparan sulfate Hepatomegaly,Skeletal dysplasia, Less than 1
VII Dermatan sulfate Short stature,Corneal clouding in 250,000
Chondroitin 4,6- Developmental delay
sulfate
Types of Mucopolysaccharidoses
Hurler
Hurler syndrome(MPS
syndrome(MPS I)
I)
-is
-is the
the most
most severe
severe ofof the
the MPS
MPS II subtypes
subtypes
-Developmental
-Developmental delay
delay is
is evident
evident by
by the
the end
end of
of the
the first
first year,
year, and
and
patients usually stop developing between ages
patients usually stop developing between ages 2 and 4 2 and 4
-followed
-followed byby progressive
progressive mental
mental decline
decline and
and loss
loss of
of physical
physical skills
skills
-Language
-Language may
may be
be limited
limited due
due to
to hearing
hearing loss
loss and
and an
an enlarged
enlarged
tongue
tongue
Hunter
Hunter syndrome(MPS
syndrome(MPS II) II)
-share
-share many
many ofof the
the same
same clinical
clinical features
features
associated
associated with
with Hurler
Hurler syndrome
syndrome (MPS
(MPS II H)
H) but
but
with
with milder
milder symptoms
symptoms
-Onset
-Onset of
of the
the disease
disease is
is usually
usually between
between ages
ages
22 and
and 44
-Developmental
-Developmental decline
decline is
is usually
usually noticed
noticed
between
between the
the ages
ages of
of 18
18 and
and 3636 months,
months, followed
followed
by
by progressive
progressive loss
loss of
of skills
skills
Sanfilippo
Sanfilippo syndrome(MPS
syndrome(MPS III) III)
-marked
-marked by
by severe
severe neurological
neurological symptoms
symptoms
-progressive
-progressive dementia
dementia
-aggressive
-aggressive behavior
behavior
-hyperactivity
-hyperactivity
-seizures
-seizures
-deafness
-deafness andand
-loss
-loss of
of vision
vision
-and
-and an
an inability
inability to
to sleep
sleep for
for more
more than
than
aa few
few hours
hours at
at aa time
time
Morquio
Morquio syndrome(MPS
syndrome(MPS IV)
IV)
-Onset
-Onset is
is between
between ages
ages 11 and
and 33
-Neurological
-Neurological complications
complications include
include spinal
spinal nerve
nerve and
and nerve
nerve
root compression resulting from extreme, progressive
root compression resulting from extreme, progressive skeletal skeletal
changes,
changes, particularly
particularly in
in the
the ribs
ribs and
and chest
chest
-conductive
-conductive and
and neurosensitive
neurosensitive lossloss of
of hearing
hearing and
and clouded
clouded
corneas
corneas
-Intelligence
-Intelligence is
is normal
normal unless
unless hydrocephalus
hydrocephalus develops
develops and
and is
is
not treated
not treated
-Physical
-Physical growth
growth slows
slows andand often
often stops
stops between
between the
the ages
ages of
of
4-8.
4-8. Skeletal
Skeletal abnormalities
abnormalities include
include aa bell-shaped
bell-shaped chest,
chest, aa
flattening
flattening oror curvature
curvature of
of the
the spine,
spine, shortened
shortened long
long bones,
bones, and
and
dysplasia
dysplasia of the hips, knees, ankles, and wrists. The bones that
of the hips, knees, ankles, and wrists. The bones that
stabilize the connection between the head and
stabilize the connection between the head and neck can beneck can be
malformed.
malformed.
Maroteaux-Lamy
Maroteaux-Lamy syndrome syndrome (MPS(MPS VI)VI)
-usually
-usually have
have normal
normal intellectual
intellectual
development
development but but share
share many
many of of the
the physical
physical
symptoms
symptoms found
found in in Hurler
Hurler syndrome
syndrome
-Growth
-Growth is is normal
normal atat first
first but
but stops
stops suddenly
suddenly
around
around age
age 88
-shortened
-shortened trunk,
trunk, crouched
crouched stance,
stance, and
and
restricted
restricted joint
joint movement
movement by by age
age 10
10
-In
-In more
more severe
severe cases,
cases, children
children also
also develop
develop aa
protruding
protruding abdomen
abdomen and and forward-curving
forward-curving spine
spine
Sly
Sly syndrome
syndrome (MPS
(MPS VII)
VII)
-Sly
-Sly syndrome
syndrome causes
causes children
children to
to be
be born
born
with
with hydrops
hydrops fetalis,
fetalis, in
in which
which extreme
extreme amounts
amounts
of
of fluid
fluid are
are retained
retained inin the
the body.
body.
-Survival
-Survival is
is usually
usually aa few
few months
months oror less
less
Genetics
Mucopolysaccharidoses
Mucopolysaccharidoses are are autosomal
autosomal recessive
recessive disorders,
disorders,
meaning
meaning thatthat only
only individuals
individuals inheriting
inheriting the the defective
defective gene gene from
from
both
both parents
parents areare affected.
affected. (The
(The exception
exception is is MPS
MPS II, II, or
or Hunter
Hunter
syndrome,
syndrome, in in which
which thethe mother
mother alone
alone passes
passes along
along the the defective
defective
gene
gene to
to aa son.)
son.) When
When bothboth people
people in
in aa couple
couple have
have thethe defective
defective
gene,
gene, each
each pregnancy
pregnancy carries
carries with
with itit aa one
one in
in four
four chance
chance that
that the
the
child
child will
will bebe affected.
affected. TheThe parents
parents and
and siblings
siblings of of an
an affected
affected
child
child may
may have
have nono sign
sign of
of the
the disorder.
disorder. Unaffected
Unaffected siblings
siblings and
and
select
select relatives
relatives of of aa child
child with
with one
one ofof the
the mucopolysaccharidoses
mucopolysaccharidoses
may
may carry
carry the
the recessive
recessive gene
gene and
and could
could passpass itit to
to their
their own
own
children.
children.
Is there any treatment?
Currently
Currently there
there is
is no
no cure
cure for
for these
these disease
disease syndromes. 
syndromes. 
Medical
Medical care
care is
is directed
directed at
at treating
treating systemic
systemic conditions
conditions and
and
improving the person's quality
improving the person's quality of life. of life.
-Physical
-Physical therapy
therapy and
and daily
daily exercise
exercise may
may delay
delay joint
joint
problems and improve the ability
problems and improve the ability to move.  to move. 
-Surgery
-Surgery to
to remove
remove tonsils
tonsils and
and adenoids
adenoids may
may improve
improve
breathing
breathing among
among affected
affected individuals
individuals with
with obstructive
obstructive airway
airway
disorders and sleep apnea. 
disorders and sleep apnea. 
-Surgery
-Surgery can
can also
also correct
correct hernias,
hernias, help
help drain
drain excessive
excessive
cerebrospinal
cerebrospinal fluid
fluid from
from the
the brain,
brain, and
and free
free nerves
nerves and
and nerve
nerve
roots compressed by skeletal and other abnormalities.
roots compressed by skeletal and other abnormalities.
-Corneal
-Corneal transplants
transplants for for significant
significant corneal
corneal clouding. 
clouding. 
-Enzyme
-Enzyme replacement
replacement therapy
therapy has
has proven
proven useful
useful in
in
reducing non-neurological symptoms
reducing non-neurological symptoms and pain and pain
ROLE OF GAGs

In
In cancer:
cancer:
Hyaluronic
Hyaluronic acid
acid may
may be
be important
important inin permitting
permitting in in tumor
tumor
cells
cells to
to migrate
migrate through
through the
the extracellular
extracellular matrix.
matrix.
Glycosaminoglycans
Glycosaminoglycans from from normal
normal cells
cells are
are completely
completely
inactive.
inactive. However,
However, glycosaminoglycans
glycosaminoglycans from from cancer
cancer cells
cells
are
are very
very active.
active. They
They are
are quickly
quickly taken
taken upup by
by both
both normal
normal
and
and cancer
cancer cells
cells and
and transported
transported toto the
the cell
cell nuclei
nuclei where
where
they
they affect
affect gene
gene transcription
transcription and
and induce
induce anan
antiproliferative
antiproliferative effect,
effect, accompanied
accompanied by by apoptosis
apoptosis (cell
(cell
death).
death).
ROLE OF GAGs

In
In atherosclerosis:
atherosclerosis:
Dermatan
Dermatan sulfate
sulfate binds
binds plasma
plasma LDL
LDL and
and itit is
is
the
the major
major GAG
GAG synthesized
synthesized by
by the
the arterial
arterial
smooth
smooth muscle
muscle cells.
cells.
ROLE OF GAGs

In
In arthritis:
arthritis:
In
In various
various types
types of
of arthritis,
arthritis, proteoglycans
proteoglycans
may
may act
act as
as autoantigens.
autoantigens.
The
The amount
amount of of chondroitin
chondroitin sulfate
sulfate in
in cartilage
cartilage
diminishes
diminishes with
with age
age while
while keratan
keratan sulfate
sulfate and
and
hyaluronic
hyaluronic acid
acid increases.
increases. These
These changes
changes maymay
contribute
contribute toto development
development of of osteoarthritis.
osteoarthritis.